Transforming growth factor β-activated kinase 1 (TAK1, MAP3K7) is a member of the MAP3K family and plays a key role in the signaling pathways of inflammation and cell survival. TAK1 is activated by a number of pro-inflammatory signals including TGFβ, TNFα, Toll-like receptor ligands and IL-1, resulting in the induction of key inflammatory and pro-survival genes such as NFκB and c-Jun-N-terminal kinases (JNKs). TAK1 inhibition induces death of cancer cells and thus, TAK1 has emerged as a potential therapeutic target for cancer and inflammatory diseases.
Prior screens by others for inhibitors of TAK1 identified the fungal metabolite 5(Z)-7-oxozeanol. However, this molecule has selectivity issues such that it targets members of the MAP2K family. Medicinal chemistry groups used the chemical scaffold of 5(Z)-7-oxozeanol as a lead molecule to generate more selective inhibitors of TAK1. Their efforts identified additional molecules namely, LYTAK1, PF-04358168, and AZ-TAK1. None of these inhibitors have been advanced clinically, largely due to selectivity issues in vivo.